Final Report Summary - IMSCIV (Immunogenicity of Mesenchymal Stem Cells in vivo)
Mesenchymal stem cells possess immunomodulatory and reparative properties. There is a large body of evidence demonstrating the capacity for MSC suppression of immune responses in vitro and an array of mechanisms have been identified. However, the ability of MSC to exert their immunosuppressive effects in vivo has been much debated within the field with some studies showing that MSC are rejected in vivo. Moreover, it remains unclear whether or not MSC are immunogenic in vivo and we hypothesised that MSC evade rejection under inflammatory but not regular conditions.
Both mouse and human MSC were characterised in vitro for their immunosuppressive effects before being utilised in in vivo assays. IFN-γ has been demonstrated to be necessary in the activation of MSC to become immunosuppressive both in vitro and in vivo. To this end MSC pre-stimulated with IFN-γ are more potent suppressors of immune responses in vitro and we have demonstrated that human MSC potently inhibit B cell proliferation and immunoglobulin production as well as T cell proliferation in vitro.
The capacity for human MSC to prevent the rejection of an allogeneic graft in vivo was examined using a novel humanised mouse model of skin and vessel graft rejection. Human MSC failed to prevent the rejection of allogeneic human skin and vessel grafts in vivo. In contrast human regulatory T cells protect allogeneic grafts and allow long term survival of such grafts in the same system. It seems likely that the difference in outcome between regulatory T cells and MSC is that the former cells are adept at homing to the lymphoid tissues where active suppression of alloreactive T cells takes place. In addition to these findings, we have evidence to suggest that MSC enhance the engraftment of PBMCs in this humanised mouse model system which is likely mediated through MSC production of trophic factors. This result is consistent with the data showing that MSC enhance HSC engraftment in vivo and is an important factor to consider in this setting.
The next step in this study will address the differences in lymphoid homing capacity between MSC and Treg and whether or not MSC can be induced to express integrins and adhesion molecules necessary for lymphoid homing in vivo.
The results from this study will contribute to the overall understanding of the effects of MSC in vivo and the mechanisms of action at play and will help to shorten the gap in the knowledge facilitating a more efficacious cell therapy. As MSC therapy is already in clinical trials for the treatment of patients with GvHD and a number of autoimmune diseases as well as kidney transplantation it is imperative that we develop a better understanding of the immunogenicity of MSC in these inflammatory settings and also a greater knowledge of how MSC exert their immunosuppressive effects in vivo.
Both mouse and human MSC were characterised in vitro for their immunosuppressive effects before being utilised in in vivo assays. IFN-γ has been demonstrated to be necessary in the activation of MSC to become immunosuppressive both in vitro and in vivo. To this end MSC pre-stimulated with IFN-γ are more potent suppressors of immune responses in vitro and we have demonstrated that human MSC potently inhibit B cell proliferation and immunoglobulin production as well as T cell proliferation in vitro.
The capacity for human MSC to prevent the rejection of an allogeneic graft in vivo was examined using a novel humanised mouse model of skin and vessel graft rejection. Human MSC failed to prevent the rejection of allogeneic human skin and vessel grafts in vivo. In contrast human regulatory T cells protect allogeneic grafts and allow long term survival of such grafts in the same system. It seems likely that the difference in outcome between regulatory T cells and MSC is that the former cells are adept at homing to the lymphoid tissues where active suppression of alloreactive T cells takes place. In addition to these findings, we have evidence to suggest that MSC enhance the engraftment of PBMCs in this humanised mouse model system which is likely mediated through MSC production of trophic factors. This result is consistent with the data showing that MSC enhance HSC engraftment in vivo and is an important factor to consider in this setting.
The next step in this study will address the differences in lymphoid homing capacity between MSC and Treg and whether or not MSC can be induced to express integrins and adhesion molecules necessary for lymphoid homing in vivo.
The results from this study will contribute to the overall understanding of the effects of MSC in vivo and the mechanisms of action at play and will help to shorten the gap in the knowledge facilitating a more efficacious cell therapy. As MSC therapy is already in clinical trials for the treatment of patients with GvHD and a number of autoimmune diseases as well as kidney transplantation it is imperative that we develop a better understanding of the immunogenicity of MSC in these inflammatory settings and also a greater knowledge of how MSC exert their immunosuppressive effects in vivo.